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Assorted Observations about the COVID-19 aka SARS-2 Pandemic: 2

April 9, 2020 25 comments

In the previous post of this series, I briefly touched on some things we still don’t fully understand about the disease caused by SARS-2 virus. Also, I am going to start calling it as the SARS-2 virus instead of COVID-19 since it displays high genetic similarity (sequence homology) to the original SARS virus. Most notably, the similarity extends to the main host protein used by both viruses to enter cells, main organs affected as well as pathological changes and diseases process caused by them. Therefore, SARS-2 is best understood as a significantly less lethal but more easily spread version of the original SARS virus. This is not to say that SARS-2 evolved from SARS- far more likely, both evolved from a common ancestor. With that out of the way, let us start by talking about ventilators or why they are of limited utility- at best.

1] During the past 2-3 weeks every politician and public figure has been incessantly talking about how we need tens of thousands more ventilators. To be fair, western countries which adopted the “neoliberal consensus” over past two-three decades ended up starving their healthcare systems to vary degrees. Hence a chronic shortage of ventilators have been a fact of life for many years especially during bad influenza seasons. While we could cerainly use more ventilators, ICU beds, more hospital beds and other medical resources in general- a large increase in those resources is unlikely to have a beneficial effect on the course of the SARS-2 pandemic. Here is why..

Based on a examination of multiple studies from countries such as Italy, Spain, UK and China- it appears that ventilators (at least as they are used right now) don’t help much with the survival of the most vulnerable group of patients. Let me put it this way, about 70-80% of people of people over 80 who end up on a ventilator due to this disease die. For those between 70-80, the number is closer to 50%, while the majority of those below 60 survive their stint on the ventilator. But why do these numbers matter. Well.. because the vast majority of those ill enough to require ventilators are over 60. To be clear, I am not claiming that nobody below 60 requires a ventilator. It is just that they are a small percentage of that age group of patients.

In other words, ventilators have poor efficacy in the age group who needs them the most. Unless significantly better protocols for medical intervention in very old and ill patients are developed, we should reconsider the wisdom of putting people above 80 with serious multiple comorbidities on ventilators- especially if there aren’t enough of them. People above 80. but without significant comorbidities. and in otherwise OK health have a better than 50% chance of survival as are those between 70-80. Any body below 70 who is not in poor health has a pretty good (better than 60%) chance of coming out alive. We should make resource allocations accordingly. I am not suggesting we go all soylent-green, but a realistic assessment of the chance of survival for each patient in the ICU with SARS-2 is necessary.

2] Talking about pre-existing conditions, it seems that the previously reported strong link of poor survival to hypertension is mostly an artifact. See.. most people above 75 have a slightly higher blood pressure than what is defined as “normal”. More relevantly, there is no evidence that blood pressures upto 150/95 are associated are bad for those over 75. Indeed, supposedly healthy systolic blood pressures below 130 have a link to slightly increased in those over 75. Having said that, there is now good evidence that the link between increased mortality from SARS-2 and cardiovascular disease and Type II diabetes is real. Infact, given that ACE2 receptors (which allow the virus to infect cells) are found on the endothelial lining of most blood vessels, it appears that the quality of baseline endothelial function is a significant factor in how ill a patient will end up.

Disturbed microvascular perfusion and tiny clots in lungs which disturb normal oxygenation of blood might also explain why so many patients in ICU due this virus have normal lung tissue compliance but really low oxygen saturation in their blood. All the cytokines released due to this infection in some patients (Il-1 and Il-6) don’t help microvascular function either. To make a long story short, very impaired microvascular perfusion and oxygen exchange in the lungs due to damaged and dead endothelial (and related) cells + severe inflammation and small clots is likely what puts most people in ICU. Clearly, we need a different and better treatment protocol for this disease than treating it as if was not different from the most common presentations of ARDS.

3] With those things out of the way, for now, let us talk about therapeutic options for SARS-2. As luck would have it, the vast majority (over 80%) who are symptomatic do not require anything more than bed-rest and anti-pyretics. This is especially the case for those below 60 years, who account for the majority of population- even in old and demographically stagnant western countries. Furthermore there is emerging evidence that the number of people who develop and recover from an asymptomatic form of this disease might be far higher than previously believed. But what about all those patients (15-20 %) who have symptoms which require some degree of medical intervention? Well.. this is where things start getting controversial.

But before we go there, let me say something else about potential treatments. It is my opinion that drugs that have to be injected or biological in nature (antibodies, recombinant proteins) are unsuitable for mass treatment of this disease because quickly scaling up facilities which make injectables or antibodies/ proteins etc is not easy. This does not mean that such drugs have no role in treating this disease. It is just that they would be most useful for people who are ill enough to be in an ICU. But as I mentioned in the earlier parts of this post, most older patients who end up in ICU end up dying- at least with current treatment protocols. The key, then, is to keep as many patients from deteriorating enough to need the ICU. In other words, we require effective orally available drugs to have a significant effect on the mortality rates due to SARS-2.

So what are the options? Well.. the most hyped drug, Remdesivir, does have activity in animal models of many viral diseases including Coronaviruses. However, it cannot be administered orally and hence will be used only in very ill patients- and that is a bad thing. See.. viral infections unlike their bacterial counterparts have to be treated early since peak viral levels are reached (and most of damage has been done) around the time people are sick enough to be require hospitalization. You can see why a drug which cannot be administered orally (and therefore used only in hospitalized patients) might provide very little therapeutic benefit in later stages of the disease. Now let us talk about Chloroquine (CQ) and Hydroxychloroquine (HCQ).

While Trump haters in media and bureaucracies are trying their best to discredit CQ and HCQ, the reality is that we have known that both drugs have decent activity against coronaviruses at concentrations achievable with normal anti-malaria or lupus dosages since 2003 (link 1, link 2, link 3, link 4). It doesn’t hurt that both drugs also have an immunomodulatory/anti-inflammatory effect. Multiple reports from China (mostly preprints) strongly suggest that normally used doses of both drugs are effective at treating SARS-2 in human beings. To be more specific, they are most effective at reducing the number of people who go on to develop severe disease if given within first 4-5 days of symptoms. No serious person is suggesting that they are miracle cures for patients ill enough to need intubation and ventilators. However, it also quite obvious that they speed up recovery from disease, reduce peak viral loads and significantly reduce the risk of complications when given early. It also helps that they can be given orally and synthesized very easily and on a large scale (by the metric ton).

Since we are already past a thousand words, I Will write about other potential drugs and therapeutic options such and convalescent plasma, monoclonal antibodies and vaccines in next post of this series.

What do you think? Comments?

Assorted Observations about the COVID-19 aka SARS-2 Pandemic: 1

April 3, 2020 27 comments

Since I have been following this viral pandemic pretty closely, and actually possess professional expertise in the topic, I thought it might be an good idea to create yet another series for posting about assorted bits of news and my musings on them. With that in mind, let us start now..

1] We still do not understand why children under 10 years of age or even teens and youth under 20 seldom get seriously ill, given that cells in their bodies also express the ACE2 protein which is used by this virus to enter cells. Sure.. man in his 80s with serious cardiovascular issues might express more of that protein on their cells, but not that much more and in any case the difference is not enough to explain the very different course of infection in the below-20 vs the above-80. Variations in amount of ACE2 expression is totally inadequate to explain why many in the younger age-groups don’t even have symptoms versus why many above 80 quickly go into respiratory failure and then cardiogenic shock so quickly.

2] Many of you might also have noticed that rich and middle-class people between 20 and 80 are noticeably less likely to develop the more serious forms of the disease than the poor or working class people. Why? Why does the course of this disease vary so much with socio-economic status? What part of being from a higher social-economic status translates into the more benign form of this illness and which aspects of being poor or working-class result in a substantially higher percentage becoming seriously ill? This is especially relevant since we do not, yet, have good and specific treatments for this infection. Also, why is mortality among blacks in USA noticeably higher than whites or latinos. Yes, this observation is based on fairly preliminary data from certain states such as Michigan and New York– but it is just too obvious to ignore.

3] We also still do not know what percentage of those infected experienced an asymptomatic or mildly-symptomatic version of the disease. This is important since the vast majority of testing in western countries is still limited to those showing some symptoms, usually serious enough to seek medical attention. But we already know that a significant minority of the infected don’t even develop symptoms and then go on to develop immunity to it without experiencing the disease. What is the percentage of those who never develop even a fever or cough serious enough to seek medical attention and why is the course of the disease so mild or nonexistent in them? What makes some people resistant to the disease even if they have no prior immunity to it?

4] How many older people who died of Acute Respiratory Distress Syndrome (ARDS) due to an unidentified reason (not bacterial pneumonia, influenza etc) in the past two months in USA, and countries such as Italy or Spain, actually died from COVID-19. I suspect that the number of such deaths might be far higher than most “serious people” are willing to accept right now. There is evidence that doctors in Italy were seeing isolated cases of serious viral pneumonia that could not be attributed to influenza or other common virus, as early as November and December 2019. In USA, this is especially obvious in certain urban areas such as Cook County and New Orleans. We require far more extensive testing of the population- both for the virus and resultant antibodies.

5] If you look at the “official” symptoms of COVID-19 or SARS-2, you will see stuff such as fever, dry cough and difficult breathing. However even a cursory glance at published data and accounts of medical professionals attending them paint a different picture. For example, symptoms such as sudden loss of smell (anosmia), some GI symptoms in elderly patients, anomalously low blood pressure, puffy allergy-like eyes carry far more diagnostic significance to this disease than typical symptoms supposedly associated with it. For example, patients who display hypotension are far more likely to progress to more serious forms of the disease than those who don’t. What is the mechanism behind these unusual symptoms and their correlation with disease severity?

In the next part, I will write about potential drug therapies to treat this infection as well as possible routes for rapid vaccine development.

What do you think? Comments?